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BACKGROUND: The influence of age at diagnosis in non-small cell lung cancer (NSCLC) prognosis is unclear. OBJECTIVES: To compare in a Brazilian cohort of NSCLC patients of different age groups: 1) The overall survival; 2) Clinical features and treatment options. METHODS: This is a retrospective cohort study using a hospital-based registry, for NSCLC patients registered in years 2000-2009. Patients were grouped into three age groups: Young adults (YA: < 40 years), middle-aged (MA: 40-64 years) and elderly (E: ≥ 65 years). Kaplan-Meier was used to estimate overall survival and Cox regression for hazard ratios (HRs) and 95% confidence intervals. RESULTS: 17,422 NSCLC patients were included: 370 YA (2.1%), 8,697 MA (49.9%) and 8,355 E (48.0%). Compared with older age groups, the YA group had a higher proportion of females, patients diagnosed with adenocarcinoma and metastatic disease (63.2%). Overall survival was longer in YA in the entire cohort and in all clinical stages (CSs) (p < 0.001). For YA, higher education level was a good prognosis factor (compared with illiterate and incomplete elementary); advanced or metastatic disease (compared with early-stage disease) and treatment based in radiotherapy or chemotherapy (CT) (without surgery), compared with treatment combinations with surgery, were poor prognostic factors. Young men (but not women) had lower HR of death compared with older groups; YA had lower HR of death in all CSs compared with patients from older groups. A higher percentage of YA were treated with surgery or CT in early-stage disease compared with older groups. Besides that, YA and MA patients treated with surgery or CT had a better prognosis than elderlies. Conclusions: In this Brazilian cohort of NSCLC patients, most young individuals were diagnosed with metastatic disease. YA presented longer survival than older age groups in all CSs, but mainly in CS I/II and III, where some patients may achieve long remissions or cure.

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Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present.

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We have investigated Amblyomin-X-treated horse melanomas to better understand its mode of action through transcriptome analysis and the in vivo model. Amblyomin-X is a Kunitz-type homologous protein that selectively leads to the death of tumor cells via ER stress and apoptosis, currently under investigation as a new drug candidate for cancer treatment. Melanomas are immunogenic tumors, and a better understanding of the immune responses is warranted. Equine melanomas are spontaneous and not so aggressive as human melanomas are, as this study shows that the in vivo treatment of encapsulated horse melanoma tumors led to a significant reduction in the tumor size or even the complete disappearance of the tumor mass through intratumoral injections of Amblyomin-X. Transcriptome analysis identified ER- and mitochondria-stress, modulation of the innate immune system, apoptosis, and possibly immunogenic cell death activation. Interactome analysis showed that Amblyomin-X potentially interacts with key elements found in transcriptomics. Taken together, Amblyomin-X modulated the tumor immune microenvironment in different ways, at least contributing to induce tumor cell death.

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We have investigated Amblyomin-X-treated horse melanomas to better understand its mode of action through transcriptome analysis and the in vivo model. Amblyomin-X is a Kunitz-type homologous protein that selectively leads to the death of tumor cells via ER stress and apoptosis, currently under investigation as a new drug candidate for cancer treatment. Melanomas are immunogenic tumors, and a better understanding of the immune responses is warranted. Equine melanomas are spontaneous and not so aggressive as human melanomas are, as this study shows that the in vivo treatment of encapsulated horse melanoma tumors led to a significant reduction in the tumor size or even the complete disappearance of the tumor mass through intratumoral injections of Amblyomin-X. Transcriptome analysis identified ER- and mitochondria-stress, modulation of the innate immune system, apoptosis, and possibly immunogenic cell death activation. Interactome analysis showed that Amblyomin-X potentially interacts with key elements found in transcriptomics. Taken together, Amblyomin-X modulated the tumor immune microenvironment in different ways, at least contributing to induce tumor cell death.

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OBJECTIVE: To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS: Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS: The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS: Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.

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OBJECTIVE: To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS: Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS: The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS: Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.

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OBJECTIVES: Several cases of bilateral diffuse pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor have been described in the literature. Nevertheless, some presentations are rare and differential diagnoses are necessary. METHODS: The purpose of this study was to perform a systematic review of the literature related to PVNS and to report a rare supra-patellar bilateral and focal presentation. We performed a systematic data review in the Pubmed Clinical Queries database using MeSH and keywords related to PVNS and tenosynovial giant cell tumor. RESULTS: Two cases of bilateral and local PVNS had been previously described, but neither was localized in the supra-patellar compartment. To our knowledge, this case report is the first to describe supra-patellar bilateral and localized PVNS of the knee. This case involves a 28 -year-old woman with bilateral localized PVNS of the supra-patellar recess of the knee. MRI showed a low-signal intensity nodule in T1- and T2-weighted images. These were associated with hemosiderin pigmentation. CONCLUSION: The most important finding of the case reported is related to rarity and location. Histopathology analysis confirmed a rare case of hemosiderin pigmentation in the capsular nodule with internal non-pigmented villous content. Lipoma arborescens in the supra-patellar form must be ruled out as a differential diagnosis since it occurs in the same site. Level of Evidence IV; Case series.

OBJETIVOS: Diversos casos de sinovite vilonodular pigmentada difusa bilateral (SVNP) ou tumor de células gigantes tenossinoviais foram descritos na literatura. Entretanto, algumas apresentações são raras e o diagnóstico diferencial é necessário. MÉTODOS: O objetivo do estudo foi realizar uma revisão da literatura relacionada à SVNP e relatar uma apresentação de forma bilateral e localizada rara na região supra-patelar. Foi realizada uma revisão dos bancos de dados do Pubmed Clinical Queries, MeSH e unitermos relacionados com SVNP e tumor de células gigantes tenossinoviais. RESULTADOS: Dois casos de SVNP bilateral e local foram descritos anteriormente. No entanto, nenhum deles foi localizado no compartimento supra-patelar. Até onde sabemos, este relato é o primeiro caso descrito de SVNP bilateral localizada supra-patelar. Apresentamos uma mulher de 28 anos com SVNP bilateral no recesso supra-patelar do joelho. A RM mostrou baixo sinal dos nódulos nas imagens ponderadas em T1 e T2, associados ao pigmento hemossiderina. CONCLUSÃO: O achado mais importante está relacionado à raridade e localização. A histopatologia confirmou um caso raro de pigmento de hemossiderina no nódulo da cápsula com conteúdo viloso não pigmentado internamente. O diagnóstico diferencial com lipoma arborescens na forma supra-patelar é necessário devido à localização comum. Nível de Evidência IV; Série de casos.

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ABSTRACT Objectives Several cases of bilateral diffuse pigmented villonodular synovitis (PVNS) or tenosynovial giant cell tumor have been described in the literature. Nevertheless, some presentations are rare and differential diagnoses are necessary. Methods The purpose of this study was to perform a systematic review of the literature related to PVNS and to report a rare supra-patellar bilateral and focal presentation. We performed a systematic data review in the Pubmed Clinical Queries database using MeSH and keywords related to PVNS and tenosynovial giant cell tumor. Results Two cases of bilateral and local PVNS had been previously described, but neither was localized in the supra-patellar compartment. To our knowledge, this case report is the first to describe supra-patellar bilateral and localized PVNS of the knee. This case involves a 28 -year-old woman with bilateral localized PVNS of the supra-patellar recess of the knee. MRI showed a low-signal intensity nodule in T1- and T2-weighted images. These were associated with hemosiderin pigmentation. Conclusion The most important finding of the case reported is related to rarity and location. Histopathology analysis confirmed a rare case of hemosiderin pigmentation in the capsular nodule with internal non-pigmented villous content. Lipoma arborescens in the supra-patellar form must be ruled out as a differential diagnosis since it occurs in the same site. Level of Evidence IV; Case series.

RESUMO Objetivos Diversos casos de sinovite vilonodular pigmentada difusa bilateral (SVNP) ou tumor de células gigantes tenossinoviais foram descritos na literatura. Entretanto, algumas apresentações são raras e o diagnóstico diferencial é necessário. Métodos O objetivo do estudo foi realizar uma revisão da literatura relacionada à SVNP e relatar uma apresentação de forma bilateral e localizada rara na região supra-patelar. Foi realizada uma revisão dos bancos de dados do Pubmed Clinical Queries, MeSH e unitermos relacionados com SVNP e tumor de células gigantes tenossinoviais. Resultados Dois casos de SVNP bilateral e local foram descritos anteriormente. No entanto, nenhum deles foi localizado no compartimento supra-patelar. Até onde sabemos, este relato é o primeiro caso descrito de SVNP bilateral localizada supra-patelar. Apresentamos uma mulher de 28 anos com SVNP bilateral no recesso supra-patelar do joelho. A RM mostrou baixo sinal dos nódulos nas imagens ponderadas em T1 e T2, associados ao pigmento hemossiderina. Conclusão O achado mais importante está relacionado à raridade e localização. A histopatologia confirmou um caso raro de pigmento de hemossiderina no nódulo da cápsula com conteúdo viloso não pigmentado internamente. O diagnóstico diferencial com lipoma arborescens na forma supra-patelar é necessário devido à localização comum. Nível de Evidência IV; Série de casos.

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OBJECTIVE: To standardize a spinal cord lesion mouse model. METHODS: Thirty BALB/c mice were divided into five groups: four experimental groups and one control group (sham). The experimental groups were subjected to spinal cord lesion by a weight drop from different heights after laminectomy whereas the sham group only underwent laminectomy. Mice were observed for six weeks, and functional behavior scales were applied. The mice were then euthanized, and histological investigations were performed to confirm and score spinal cord lesion. The findings were evaluated to prove whether the method of administering spinal cord lesion was effective and different among the groups. Additionally, we correlated the results of the functional scales with the results from the histology evaluations to identify which scale is more reliable. RESULTS: One mouse presented autophagia, and six mice died during the experiment. Because four of the mice that died were in Group 5, Group 5 was excluded from the study. All the functional scales assessed proved to be significantly different from each other, and mice presented functional evolution during the experiment. Spinal cord lesion was confirmed by histology, and the results showed a high correlation between the Basso, Beattie, Bresnahan Locomotor Rating Scale and the Basso Mouse Scale. The mouse function scale showed a moderate to high correlation with the histological findings, and the horizontal ladder test had a high correlation with neurologic degeneration but no correlation with the other histological parameters evaluated. CONCLUSION: This spinal cord lesion mouse model proved to be effective and reliable with exception of lesions caused by a 10-g drop from 50 mm, which resulted in unacceptable mortality. The Basso, Beattie, Bresnahan Locomotor Rating Scale and Basso Mouse Scale are the most reliable functional assessments, and but the horizontal ladder test is not recommended.

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Our goal was to develop a novel technique for inducing Achilles tendinopathy in animal models which more accurately represents the progressive histological and biomechanical characteristic of chronic Achilles tendinopathy in humans. In this animal research study, forty-five rabbits were randomly assigned to three groups and given bilateral Achilles injections. Low dose (LD group) (n = 18) underwent a novel technique with three low-dose (0.1mg) injections of collagenase that were separated by two weeks, the high dose group (HD) (n = 18) underwent traditional single high-dose (0.3mg) injections, and the third group were controls (n = 9). Six rabbits were sacrificed from each experimental group (LD and HD) at 10, 12 and 16 weeks. Control animals were sacrificed after 16 weeks. Histological and biomechanical properties were then compared in all three groups. At 10 weeks, Bonar score and tendon cross sectional area was highest in HD group, with impaired biomechanical properties compared to LD group. At 12 weeks, Bonar score was higher in LD group, with similar biomechanical findings when compared to HD group. After 16 weeks, Bonar score was significantly increased for both LD group (11,8±2,28) and HD group (5,6±2,51), when compared to controls (2±0,76). LD group showed more pronounced histological and biomechanical findings, including cross sectional area of the tendon, Young's modulus, yield stress and ultimate tensile strength. In conclusion, Achilles tendinopathy in animal models that were induced by serial injections of low-dose collagenase showed more pronounced histological and biomechanical findings after 16 weeks than traditional techniques, mimicking better the progressive and chronic characteristic of the tendinopathy in humans.

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